Current Research into a Cure for Type-1 Diabetes

Sunday, July 19, 2015

In my opinion, artificial pancreas (AP) technology was the single most important technology of the American Diabetes Association Scientific Sessions this year. There were many papers, posters, and presentations on artificial pancreases and related technologies (such as continuous glucose monitoring, stable glucagon, etc.) Nothing generated more Twitter buzz.

This blog posting attempts to summarize a little of the research presented. There was way too much for me to cover it all, and so this posting gives light coverage to the most important news.

My overall summary is that we are no longer talking about if there will be an AP. The question is: when there will be an AP, and how many APs, and how many different types of technology they will use. I continue to be heartened by:
(a) the progress made by AP research projects over the last few months (and years)
(b) the large number of new companies entering the field
(c) the product roadmap announced by Medtronic as they move their existing partial AP to a full AP.

The AP world is more and more driven by commercial considerations, rather than research considerations, and that is a strong signal that we are close to general availability. (Close meaning years, but not too many of them.)

This tweet summarizes my thoughts, as well:

“Closing the loop is no longer a mystery; it’s not a puzzle. We just have to do it.”

It's a little hard for me to figure out exactly where they are, and I have not found any articles in scientific journals. However, it appears that earlier this year they ran a two day test on one person, and got quite good results. The average BG was 125. Based on that they are hoping to run two clinical trials (called APPEL 4 and APPEL 5) later this year. They hope those trials will used as the basis for European "CE" approval.

Maybe a Third?

They haven't started recruiting yet, but this looks like a phase-II trial for yet a third bi-hormonal artificial pancreas. I'll blog more fully if they start recruiting:

The Medtronic 670G, as announced, will be an "all but meals" style, single hormone artificial pancreas, available in the United States in April 2017. As far as I know it is the most powerful AP with a clear commercial delivery date. For comparison, the 640G is already available in Europe, but does not prevent "highs," only "lows".

Bigfoot is a one year old company. They had a very successful ADA and generated a lot of "buzz", which this tweet tries to summarize.
From https://twitter.com/diaTribeNews/status/604309757093011456:
@BigfootBiomed acquires Asante pumps! Goal to enter pivotal trial of full #artificialpancreas system late 2016

A "pivotal" trial is industry-speak for a phase-III clinical trial. What they are saying is that they hope to start phase-III trials of an AP next year. That would put them shoulder to shoulder with Medtronic and front running bihormonal research projects. Even if they are overly optimistic, and they actually start those tests in 2017, they are still not that far away from a commercial AP.

But even more promising (to me) is that Bigfoot feels like a tech start up, not a medical device company. It feels like Silicon Valley rather than Washington D.C. I can't tell if that's a marketing strategy or the truth, but if you look at the founders, look at the tactics (reuse the failed carcass of another project), and the strategy: it really does look like the way things happen "out here".

When a company like that can successfully create an AP, it means that APs are technology gizmos, and not medical devices, and technology products can improve much more quickly than medical products. I'm sure the FDA will have something to say about it, but even if Bigfoot is just a 20% step in the direction of Silicon Valley, that's going to "light a fire underneath" some medical device companies.

This is based on AP research done at the University of Virginia which I have reported on before.

Comparison

There was some debate at ADA about which was better: single hormone artificial pancreases, or bihormonal artificial pancreases. My first reaction to this debate was this: who cares? Either one is so much better than what we have now, let the people who like insulin only APs develop those, and let the people who like insulin and glucagon APs develop those, and let the market decide, or maybe let the market decide that there is room for more than one AP technology. I mean some people have cable while others have satellite, why not the same with APs? Have we learned nothing from the death of communism? Let the market decide, as fed by the strongest proponents of each system.

My second reaction to this debate was that it can never be resolved by research. The data we have now is pretty clear: single hormone APs result in average BG numbers about 10 points higher than dual hormone APs (for example mid 130s vs mid 140s). However, dual hormone APs are more complex to manufacture, more complex to operate, and involve the tiny risk of long term, very low dose glucagon (and that risk is unknown, and will remain unknown for years). So some people are going to say dual hormone is 10 points better than single hormone, end of story. But others will say, mucking about with refilling two reservoirs is just not worth 10 points. And neither of these opinions is right or wrong, they are just different. And always will be.

However, even if research cannot answer a question, it can still inform the discussion, and there have been some papers directly comparing the two systems. The following tweet is one summary, but the links to the abstracts below contain more data.

Joshua Levyhttp://cureresearch4type1diabetes.blogspot.compublicjoshualevy at gmail dot comAll the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Saturday, July 4, 2015

The American Diabetes Association's annual conference is the largest scientific gathering covering diabetes in the United States. Even though most of the conference is aimed at type-2 diabetes, the part covering type-1 diabetes is still overwhelming. About 18,500 people attended this year.

I was not able to go this year (it was in Boston), so I tried an experiment. I closely followed tweets and news coverage of the convention. I thought of myself as a wire service and the tweeters/bloggers/reporters at the conference as my freelancers. I was reading about 1000 tweets a day from the following sources: #2015ADA, #ADA2015, @diaTribeNews, @DiabetesMine, @sarhoward, @AmyDBMine, and @kellyclose.

I'm going to summarize these in two postings. This posting has four sections: an overview, research in people aimed at a cure, research which has cured mice, and non-cure related research. The next posting will cover artificial pancreas research. There was a lot.

ADA includes a sea of expert opinions, but also the results of many experiments. So it is especially important to remember these words by Robert H. Mathies (Often incorrectly attributed to von Braun):

"One experiment is worth a thousand expert opinions"

Overview

You can read the abstract to every poster session at the link below, and most of them have a PDF of the poster itself:http://ada.apprisor.org/epsSearchADA.cfm
Although the posters are easy to search, I cannot set up a link to one once I find it. So I have put in the poster number (like 1234-P or 42-LB). Go to the link above and search for the number to find the abstract and the poster itself, when it's on line.

A big theme of the conference seemed to be treating patients rather than numbers, and generally emphasizing holistic care, and looking at more complex (and realistic) measures of health, than single numbers. For me, this was typified by the following tweet which I saw repeated several times: "A three-month average cannot tell the full story." I think the tweet originated with @kellyclose (diaTribe), but I'm not sure.

ViaCyte's Phase-I Trial is 1/10th Enrolled
JDRF sent out this update on ViaCyte's Phase-I clinical trial:
There are as many as 4 people in SoCal currently testing @ViaCyte's experimental devices. That's progress.https://twitter.com/JDRF/status/606910609695735808
The trial plans to enroll 40 people, so it sounds like they are 1/10th of the way there (depending on exactly what "as many as" really means).

1102-P: Immune Modulation of Stem Cell Educator Therapy in Caucasian Type 1 Diabetic Subjects
This poster contained information from the Phase-II trial of the Stem Cell Educator currently running in Spain. I will blog more on this later, but for me, this poster had a "split personality". On the one hand it was reporting on good changes to the immune system in people who got the treatment. More good immune cells; less bad ones. It looks like good news: the Educator is changing the immune system for the better. On the other hand, there is none of the patient-focused data that would show progress to curing type-1 diabetes. No data on C-peptide production; no improvements to A1c; no changes reported in insulin use. (And the phase-I trial did have this kind of data. So I'm not sure if this poster just focused on the immunology details, and a future paper will include C-peptide data, or if the C-peptide data in this second trial was not worth reporting.)

Poster 1812-P:
A new peptide (small protein like chemical), called KGYY15 is a honeymoon cure of type-1 diabetes in NOD mice.

Poster 1804-P:
Amylin Induces CD4+CD25+Foxp3+ Regulatory T Cells
Amalyin is a hormone given to type-2 diabetics, but there is some research to show that it would also help type-1 diabetics maintain better BG and A1C numbers. This poster reports that it also increases the number of a specific type of helpful T cell. This work is related to human trials, because at least two groups are "growing out" CD4+CD25+ T cells in the hopes that they will be a honeymoon cure to type-1 diabetes. Obviously, if Amylin has the same effect in people as these researchers found in mice, and if the researchers "growing out" these cells in people get a good result, that's good all around.

Poster 1818-P: Local Expression of CCL21 in Pancreatic Islets Prevents Autoimmune Diabetes in Mice and Is Associated with Beta Cell Antigen-Expressing Lymphoid Stromal Cells
The poster was not on line, but the abstract was. CCL21 (another small protein) prevented type-1 diabetes in NOD mice.

Poster 1826-P:
Prevention or Early Cure of Type 1 Diabetes by Intranasal Administration of Gliadin in NOD Mice
The poster was not on line, but the abstract was.

Poster 218-LB:
Nasal Administration of Novel Insulin Degrading Enzyme Inhibitor Ameliorates Autoimmunity in [NOD mice]
The poster was not on line, but the abstract was.

For those keeping track, that is six mouse cures presented at one scientific meeting. For me, the interesting point will be: how many eventually get into human trials. One? None? Only time will tell.

Non-Cure Research, But Interesting To Me

FDA Bullshit
This tweet really angered me:
Stayce Beck of @US_FDA calls out companies for not including kids in pediatric studies, says it's opposite of what agency wants.https://twitter.com/DiabetesMine/status/607291226597883904
This is completely two-faced, as far as I'm concerned. Every researcher I interact with wants to have more kids involved in their studies. Especially for honeymoon research, there are just so many more kids around. But they can't because the FDA has specific regulations which prevent it! It's the FDA who is creating and enforcing unreasonable limitations, and to turn around and "blame the victim" is scummy. And the FDA's policies on kids in research does victimize researchers (as well as children) because it really slows down research and at the same time limits approved options for treating kids.

(I don't think I've ever sworn on this blog before, but this quote -- if true, and if really said by an FDA employee -- really deserves it. I'm proud to say: I call bullshit on that!)

Type-1 vs. LADA
There were several posters and papers which reported on differences between people diagnosed with type-1 as kids, and those diagnosed with it as adults. Some researchers consider these to be the same disease with slightly different natural histories (sort of like chickenpox vs. shingles) while others consider these two to be two different diseases (with different causes or "etiologies"). All of the following posters described differences in early onset type-1 diabetes and late onset type-1 diabetes:
Poster 1801-P: Heterogeneity in Type 1 Diabetics Is Defined by Contrasting C-Peptide Declines, Autoreactive T Cell Burdens, and Metabolomic Differences
Poster 1819-P: IGRP-specific CD4+ T Cell Response Is Distinct between Adult-Onset and Juvenile-Onset Type 1 Diabetes Patients
Poster 212-LB: Anti-paralemmin 2 Antibody as a Novel Antibody for Latent Autoimmune Diabetes in Adults
Poster 1723-P: Determinants and Prognosis of Early- vs. Late-Onset Islet Autoimmunity

Poster 1737-P:Ecological Study between the Incidence of Type 1 Diabetes and Geochemical Data in Sardinia: Negative Correlation with Zinc and Copper
Sardina has a high rate of type-1 diabetes, and the rate is not the same throughout the island, so these researchers tried to correlate various heavy metals in the environment to the higher type-1 rates in the same areas. Higher levels of Zinc and Copper were found to protect people from type-1 (ie. higher levels of these metals correlated with lower levels of type-1), and no correlation was found for the rest of the metals they researched. Here are the metals they checked: As, Be, Cd, Co, Cr, Cu, Mn, Ni, Pb, Sb, Se, Sn, Th, Tl, U, V, Zn.https://twitter.com/sarhoward/status/607251283796443136

1732-P:Unexpected Stability of Type 1 Diabetes Incidence in a U.S. Cohort, 1994-2010
Basically, they found a type-1 rate of about 1 in a 1000 (lower than expected) and found that this number was going up before 2002, but going down after that. That's not the common wisdom. Most researchers think the type-1 rate is steadily going up.

For the opposite viewpoint: 1735-P:The Incidence of Type 1 Diabetes Mellitus in Romanian Children Aged 0-14 Years Increased Constantly
(No poster, but a very nice graph in the abstract.) This is the opposite finding as the previous poster, but this is the conventional wisdom about what is happening. The two posters covered different geographical areas.

978-P:Dance-501 Inhaled Human Insulin
Research results from another inhaled insulin. Phase-I trial, 24 people, type-2 diabetics. Affrezza might have competition someday, and that can only be good, in terms of more choices for type-1s.

Big claim by Dr. Dandona: “Predict w/ this 3x therapy (insulin, GLP-1, SGLT-2) we can get at least 50% of #T1D patients [below] 6% A1c"
If he is right (and that is a big "if"!) this will be a big change in the treatment of type-1 patients. Right now, insulin-only treatment is normal, and A1Cs are rarely this low. GLP-1 is widely used in type-2, but not widely used in type-1. In my opinion, the results of the GLP-1 in type-1 studies that we do have, show some improvement, but not a lot. SGLT-2 is even farther away from type-1 use, as there is even less research. But again, in my opinion, the improvements that have been seen are real (in early testing) but not dramatic. However, this doctor thinks that by combining these two treatments, we can lower A1c between 1 and 2 points; that would be great, if it were true, and if type-1s were willing and it was safe to take both drugs for the rest of their lives.https://twitter.com/diaTribeNews/status/607664169408733184

Joshua Levyhttp://cureresearch4type1diabetes.blogspot.compublicjoshualevy at gmail dot comAll the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Tuesday, May 26, 2015

Mesenchymal Stromal Cells (MSC) are the stem cells in your bone marrow. Stems cells can grow into beta cells, and some researchers think they can modulate the immune system (they generate one or more chemicals that cause the immune system to stop attacking beta cells). So it's possible that stem cells might resolve both cure issues at once. They might be able to regenerate beta cells and stop the autoimmune attack. That is what these researchers hope.Results From a Phase-I Trial

These researchers, at Uppsala University Hospital in Sweden, ran a phase-I trial, randomized and with a control group, but not blinded. There were 10 people in the treated group, and 10 in the control group. MSCs were harvested from a patient, treated externally, and then put back in that same patient. No immunosuppression was used, and I don't think the people were ever hospitalized (the work was done in a clinic). Data was collected on insulin usage, A1c, fasting C-peptide, and post meal C-peptide, among other measures.

Fasting C-peptide measures how much insulin your body is generating as background. It's measured while fasting, usually first thing in the morning. This is your natural basal insulin. Post meal C-peptide measures how much insulin your body is generating in response to carbohydrates. It's measured after eating a meal with a known carbohydrate content. This is a body's natural insulin bolus.

My summary of the results are as follows. In all cases the paper is comparing data measured 10 weeks after the treatment (which the paper considers starting or baseline data) to data measured 1 year after treatment (which the paper considers resulting data):

Fasting C-peptide, A1c, and insulin usage did not significantly change for either group, and there was no significant differences between the groups.

Post meal C-peptide levels for the untreated group dropped about 12%. Dropping is bad, but it's also normal during the honeymoon phase. In the treated group, C-peptide numbers rose 5-10%, and that represents improvement. The difference between the two groups was statistically significant.

There were no safety issues.

Discussion and Opinions

Confirming that the procedure was safe is a good thing, of course, and is the official goal of a phase-I trial. But this is a procedure that's been done for decades to treat other diseases (especially cancer), so no surprise that it is safe.

I was a little surprised at how consistent the insulin usage, A1c numbers, and fasting C-peptide numbers were. I assumed that A1c would still be high from diagnosis and would drop, and that insulin usage would rise to the end of the honeymoon, and that fasting C-peptide would drop. None of that happened during the course of the honeymoon.

The important results are the post meal C-peptides. For this data, higher numbers are good, because they mean the body is generating more of it's own insulin. In untreated people those numbers dropped about 15%, which is normal for the first year after diagnosis. The treated people saw a rise in their C-peptide. There is no doubt that is good news, but it did not have an impact on the treated people. Specifically, they were still injecting the same amount of insulin, and their A1Cs did not improve. So it's a small effect.

My memory is that I've seen this level of result several times, for several different drugs, over the last two years or so. I think I was much more excited about them in the past. Part of my lack of excitement is that the treatments with these results that I saw a few years ago have not progressed. They don't give better results in more recent studies. That might be because the research is taking longer than expected, or it might be that getting a small result is much easier than getting a useful (to patients) result. But in any case: I haven't seen forward progress in other treatments with similar initial results, so I've become less excited about these kinds of results, in general.

So in general, these results go in my "good start, but more is needed" category of results.

Joshua Levyhttp://cureresearch4type1diabetes.blogspot.compublicjoshualevy at gmail dot comAll the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Friday, May 8, 2015

I have decided, for 2015 at least, to do quarterly updates for Artificial Pancreas research. The area is moving forward so quickly that I think that quarterly updates are warranted.

The term "artificial pancreas" refers to using a continuous glucose monitor (CGM) to feed data to a computer, which controls an insulin pump, and in some models, a glucagon pump as well. Artificial pancreas refers to using existing technology in all these areas, but connecting them together so that a person does not need to worry about counting carbs or blood glucose levels. It is all done automatically. Most people do not consider this a cure, but I follow AP research because some people do consider it a cure. There is no doubt that such technology would be a huge step forward in treatment, and would largely prevent "dead in bed" due to low blood glucose events.

An earlier version of this blog had the wrong dates for future Medtronic product releases. I'm sorry about that. This posting has the correct dates. Thanks to Tamar Sofer-Geri for finding the mistake.

Artificial Pancreas Update for April 2015

The JDRF uses a 6 step model to describe milestones on the way to the fully featured artificial pancreas that we all want. You can read about those milestones here: http://jdrf.org/research/treat/artificial-pancreas-project/.
So when I refer to "step 1" and "step 4" and so on in this blog, I'm referring to the steps described by JDRF.

Corporate News from Medtronic

Back in January, Medtronic made the following product announcements:

The 640G (predictive low glucose suspend) will ship in Europe in April 2015.

First, the 640G is a step 2 Artificial Pancreas, so it will predict and avoid low blood glucose events.

Second, the 670G (depending on exactly how it turns out) could be a step 3 or 4 device. That means it will predict and avoid both low BGs and high BGs, but not cover meals automatically.

Third, it means that Medtronics believes that the FDA's previous approval delays will stop:

There was a 2.5 year delay (from European approval to US approval) for the 530G.

Medtronics expects a 1 year delay for the 640G.

Medtronics expects a 1 year advantage (US before Europe) for the 670G.

I hope they are right about this! FDA's delays in earlier AP approvals are one of the major reasons AP development has been slow, and European availability is ahead of us. If the FDA is able to fix this problem over the next few years, that is a huge piece of good news for all AP companies and ultimately, all AP users.

There are only a few paragraphs on AP research, and my rough translation of them is this:

Tandem is currently experimenting internally, and not on people, with both predictive low glucose suspend (step 2 AP) and predictive high glucose dosing(step 3 AP). In the second half of 2015 they will start the paperwork to run a clinical trial testing predictive low glucose suspend. Based on discussions with the FDA at that time, they will have better idea of how many clinical trials will be required for approval (and therefore how long it will take). Also they will have a better idea about testing both the predictive low suspend and high dosing at the same time, or release one and then the other.

Bihormonal AP Update from CarbDM's Diabetes Summit

I attended CarbDM's "Diabetes Summit" in Silicon Valley last month. It was wonderful, even though I could not stay to the end. Listening to the morning speakers was very informative, but in this blog I'm going to limit myself to discussing Dr. Ed Damiano's talk.

Dr. Damiano is working on a bihormonal (insulin and glucagon) AP, called the "Bionic Pancreas". The key piece of information from his talk was that they will finish the current round of phase-II trials on April 27th (that's the last day of data collection). Another round of studies is planned for the second half of 2015. For next year, the plan is to create a device that can be sold and spend the rest of 2016 and 2017 testing it.

Dr Damiano reported on results from several clinical trials (adults and children who use the AP under different circumstances). For all these studies, the numbers were great (in my opinion). They averaged in the low 140s or high 130s in different trials.

There were some other interesting tidbits: the daily dose of glucagon used by people on this bihormonal AP was between 1% and 3% of the dose used in a single "rescue" injection, so a relatively small amount. Also, the amount of insulin used by people on the AP was about the same as people in the control group. So it's clear that the bihormonal AP is using insulin more efficiently, not just using more insulin.

Joshua Levy http://cureresearch4type1diabetes.blogspot.com publicjoshualevy at gmail dot com All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Sunday, April 19, 2015

ATG is Anti-Thymocyte Globulin, a biological agent used to lower immune reactions.
GCSF is Granulocyte Colony-Stimulating Factor, a biological agent which causes bone marrow to generate more stem cells and more immune cells, and put them into the blood stream. It is sometimes called G-CSF, and the exact product being used is Neulasta.

This is a three armed study. Each group will have at least 28 people. The first will get ATG. The second will get ATG and GCSF. The third will get a placebo. The ATG will be given twice, one day apart. The GCSF will be given six times, two weeks apart. They started recruiting in December 2014, and hope to finish collecting their data in October 2016. The primary outcome (the most important result they will measure) is C-peptide generation after a meal as measured a year after treatment. There are no secondary outcomes listed, however I've been told they will track A1c, insulin usage, low BG, adverse effects, and infection rates as secondary outcomes.

They are recruiting in at least six different locations, all over the United States. Although it's not listed on the clinical trial site, Stanford is recruiting for this trial, and they are planning on adding UCSF soon as well. The list (with contact information) is in the Clinical Trial Record below. Patients must be between 12 and 46, and have been diagnosed within a 100 days,so this is a honeymoon trial.

Funding for this trial comes from several US government agencies, JDRF, ADA, Helmsley, and two commercial companies: Sanofi and Amgen.

Discussion About Previous Results

For me, the most important question in a phase-II trial is: "What happened in the phase-I trial?" If there was a phase-I trial. For this treatment, there was and it included a placebo group. The results were good, but not great, from the point of view of curing type-1 diabetes. Over the years of the trial, the placebo group had lower C-peptide levels (meaning they lost the ability to make their own insulin). This is what would be expected during the years after diagnosis. The treated group's C-peptide levels stayed about the same.

Obviously, an optimist will look at those results, and say "they stopped the loss, this is good, and the earlier we can use this, the better it will be". A pessimist would say "they had type-1 when the trial started; they had it when it was over; there was no real improvement".

And here is the most important graph from those results, you can see that treated people stayed the same (dark line at top) while untreated people got worse (lighter line below):

The full paper is here: http://www.jci.org/articles/view/78492.
Thanks to the The Journal of Clinical Investigation for making the whole paper available on line.

Joshua Levy http://cureresearch4type1diabetes.blogspot.com publicjoshualevy at gmail dot com All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Friday, April 10, 2015

Kickstarter is a web site which "crowdsources" funding for creative projects. This is called "crowdfunding". In my opinion is is an important part of a creative explosion made possible by the world wide web. If someone wants to write a book, they can run a Kickstarter to fund printing it, before they spend the time writing it. They could promise people who give $20 a copy of the book, and promise people who give $40 an autographed copy of the book, and allow people who give $200 to name a minor character in the book. That sort of thing. It opens up whole new areas of creativity, by lowering the financial risk to creative people.

You can go to kickstarter.com and search for "diabetes" to see projects which have something to do with diabetes. Kickstarter is not the only site that does this kind of crowdfunding. Gofundme.com and indiegogo.com are similar.

This web site is trying to take the ideas which worked so well for Kickstarter, and apply them to funding of type-1 diabetes research projects. They've got six projects on their web site right now, so you can see how it works. Of the six projects, one is fully funded, and one other is a sort of "internal project" to fund the web site itself. The other projects are in process. Projects must be completed in a year, and are limited to $60,000, so I doubt these guys are going to fund any human trials. However, all research needs to start somewhere.

Discussion and Opinion

There is no doubt in my mind, that the reason some people don't like giving money to large, impersonal organizations (like JDRF) is that they don't have any connection to where the money ends up. If I give $1000 to JDRF, they end up giving that money to 300 different research projects. I can read about the highlights of JDRF funding in general, but I don't feel a personal connection to any of it. That really bothers some people. (I'm just using JDRF as an example here, most large charities work this way. Discussion of "earmarking" is below.)

This system is very much the opposite. I know exactly where my $1000 goes, and get updates from the researcher, and see exactly what gets published and so on. When I donate, I automatically become part of a community of people who care about that specific research project; there is a social aspect to it.

There is also a "middle of the road" option. For many charities, including JDRF, you can gain that personal connection by "earmarking" your donation to a specific research project or specific research area, but that requires a little extra work, and does not have the social aspects that The Diabetes Connection has. The Diabetes Connection has forums for each specific research project; JDRF has fewer opportunities for interaction, and they are for the charity as a whole, not specific research projects.

I certainly am not going to argue that one system is better than another; for one thing, I think different people will be attracted to different systems. I like the idea of different models of charitable giving completing with each other to see which works best, and also available for different people who like different ways of donating money.

But it is also important to remember the risks. The Diabetes Research Connection has not yet been reviewed by CharityNavigator.org, and doesn't have a track record to evaluate (either from a research point of view or a financial point of view). Finally, the whole idea of pushing funding decisions down to the individual contributor has some large risks. Charity organizations, especially the larger well established ones, have resources and processes to evaluate research proposals. Individual contributors rarely do.

I want to thank Brian Braxton for first bringing this to my attention.

Joshua Levyhttp://cureresearch4type1diabetes.blogspot.com publicjoshualevy at gmail dot com All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Sunday, March 15, 2015

Tocilizumab (brand name: Actemra, often shortened to TCZ) blocks the action of IL-6 which is a part of the immune system. It has been approved in the USA since 2010 for use against Rheumatoid Arthritis, which, like type-1 diabetes, is an autoimmune disease. The hope is that since it works on one autoimmune disease, it will work on another. Usually the drug is given as an IV drip (which requires a clinic visit), but recently a subcutaneous injection was approved. Subcutaneous injections are the same type of injection as used for insulin.

Tocilizumab Starts a Phase-II Trial

The trial is straightforward. It is placebo controlled, double blind. Of 108 patients in the trial, 2/3s will get the treatment and 1/3 will get the placebo. The drug is given via IV once a month for a total of seven treatments. The last data will be collected 2 years after the first treatment. Researchers will gather data on C-peptide production, A1c numbers, and insulin usage. This study is being funded by the National Institute of Allergy and Infectious Diseases (NIAID) and done in cooperation with Immune Tolerance Network (ITN), and the Diabetes TrialNet. They are recruiting honeymoon diabetes (within 100 days of diagnosis), and expect to have ten different sites all over the US. They hope to have results by August 2018.

The interesting part, at least to me, is how they are handling recruiting children. They have the standard problem of recruiting honeymoon type-1 diabetics: The FDA often requires a trial in adults before you can run a trial in children. Of course, this is a particularly silly requirement for a drug (like Tocilizumab) which has already been approved for use in children. In order to get around this restriction, the researchers organized their trial in the following way: The first 30 patients will all be adults. After those adults have been treated for 12 weeks, the accumulated safety data will be reviewed, and (hopefully) the rest of the trial will be open to people of all ages. But the downside is the delay caused by limiting recruitment to adults for about 30 out of 108 patients. Finding adults within 100 days of diagnosis is a lot slower than finding children.

However, they are planning on adding many more sites, including these in California:
University of California San Francisco -- San Francisco, California, USA -- Rebecca Wesch 415-476-5984 weschr@peds.ucsf.edu
Stanford University -- Stanford, California, USA -- Trudy Esrey 650-498-4450 tesrey@stanford.edu

Many more are listed in the clinical trial record. The web site is below.

Tocilizumab's safety profile is pretty good. This study:http://arthritis-research.com/content/13/5/r141
looked at serious adverse events and "plain old" adverse events in 8 different clinical trials run for Tocilizumab's rheumatoid arthritis approval. Five of them were phase-III trials. You can look at the details, but basically serious adverse effects where the same in placebo, low dose and high dose. For "plain old" adverse effects, high dose was about 10% higher than placebo, and low dose in between the two.

If Tocilizumab does prove effective, there are several other drugs available which work by blocking IL-6, and presumably they would be worth testing as well: Sarilumab, Olokizumab, and Elsilimomab are examples.

Extra Bits and Pieces

I have not found a "cured in mice" type experiment for Tocilizumab, but it has been tested in human tissue samples. There are some mouse studies from the 1990s showing that IL-6 does effect the development of autoimmune diabetes in NOD mice.

Clinical development for this drug took about 13 years until it became available in the US, and it was first created about 25 years before commercial availability.

In 2011, the FDA approved Tocilizumab for use in children as young as two years old.

If Tocilizumab does prove effective, there are several other drugs available which work by blocking IL-6, and presumably they would be worth testing as well: Sarilumab, Olokizumab, and Elsilimomab are examples.

Joshua Levyhttp://cureresearch4type1diabetes.blogspot.com publicjoshualevy at gmail dot comAll the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

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This blog discusses cures and preventatives for type-1 diabetes that are either in human trials or just about to start. Treatments for diabetes are not generally discussed here, unless they can turn into a cure or a preventative. My definition of a cure is this:1. Blood sugar control without testing and with doctor's visits 4 times a year, or less. Any cure must result in an average lifespan close to normal.2. Does not require a lifetime of immunsuppressive drugs, so it is not trading one treatment for another. (but a couple of operations, or a short course of drugs is OK)Obviously, this is my personal definition of a cure; yours may differ.Because a cure for type-1 diabetes is likely to involve a combination of several different drugs or treatments, I try to follow research into anything which may be an important part of the cure.

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I don't work for a company involved in medical research; I never have.

I don't get paid in any way by any company doing medical research; I never have. And that includes free samples, free travel, or free anything.

None of the hours that I have put into my blog, or the posts that I make to any web site, has ever been paid for, nor have I gotten anything free. (Except for some very nice and heart felt thank-you emails, and those are worth more than money.)

My daughter has type-1 diabetes and participates in clinical trials. I sometimes report on trials that she participates in.